tbuckley/cabot-search huggingface dataset:
Prediction of early treatment failure of second-line nal-iri/5-FU/FA in patients with advanced pancreatic adenocarcinoma (AIO-PAK-0216).
Authors: Meinolf Karthaus, Nikolaus Ansorge, Gleb Barmashenko, Christof Burkart, Thomas Decker, Thomas Jens Ettrich, Anke Gerhardt, Sabine Hoefling, Lutz Jacobasch, Michael Koenigsmann, Sebastian Räth, Markos Schulte, Nadine Schulte, Andreas Schwarzer, Gabriele Margareta Siegler, Dirk Waldschmidt, Manfred P. Lutz
Journal: Journal of Clinical Oncology (2023)

721 Background: Second-line Nal-Iri/5-Fluorouracil/Folinic Acid (Nal-Iri/5-FU/LV) increases overall survival of unselected patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC) after gemcitabine-based therapy. It is unknown, which pts will likely benefit or could probably profit more from alternative approaches. Methods: In this prospective trial, 156 pts with locally advanced or metastatic PDAC were included for treatment with biweekly Nal-Iri/5-FU/LV (70 mg/m², 2.4 g/m², 400 mg/m²) after failure of 1st line chemotherapy with Gemcitabine/nab-Paclitaxel, with comprehensive evaluation of prior treatment characteristics, potential predictive factors, and quality of life. Primary end point is the correlation of time to treatment failure (TTF) of 1st and 2nd line therapy. Moreover, translational research was done to measure and evaluate biomarkers in blood and tumor tissue. Here, we explore patient characteristics in two subgroups with short or long treatment duration, with the aim to evaluate potential predictive factors for further analysis. Results: 139 (90%) of the 156 pts included between 03/2018 and 07/2021 in 40 German sites received medication. End of treatment is documented for 128 pts, with 5 still on treatment as of 05/2022 Mean (±SD) treatment duration was 15.5 weeks or 7.7±7.1 cycles (median 7 weeks; 5 cycles). 37 (25%) pts received ≥ 10 cycles. The median was used to separate two subgroups of short and long treatment duration (STD, ≤ 5 cycles, n=66 (52%) vs. LTD, &gt; 5 cycles, n=62, (48%)). Reasons for treatment discontinuation clearly differed between the two subgroups: death in 9% vs. 3%, toxicity in 9% vs. 2%, unrelated medical condition in 12% vs. 2%, and progressive disease in 46% vs. 73%, respectively. Investigator´s decision was a reason for discontinuation in 6% vs. 5%. Pts with STD had a lower performance status (ECOG 1 or 2 in 74% vs. 52%, ECOG 0 in 20% vs. 44% in STD vs. LTD group), lower albumin levels (below normal in 36% vs. 24.2%) and were more likely to suffer from liver metastases (overall 82% vs. 66%). There were no relevant differences with regard to age, sex and tumor burden (number of metastases or CA19-9 levels). Conclusions: Early treatment discontinuation was primarily associated with patient-related factors such as low performance status, low albumin levels and comorbidities, characteristics which could be used to spare patients from treatment with an unfavorable risk-to-benefit ratio. In contrast, surrogate markers for tumor burden did not correlate with treatment success. Clinical trial information: NCT03468335 .
The role of Smad4/TGFB signaling in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC).
Authors: Hannah Yoo, Anna Means
Journal: Journal of Clinical Oncology (2023)

748 Background: Pancreatic cancer ranks 4th among cancers as a cause of death in the United States and 85- 90% of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated 2 major types of precursors to PDAC including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN); the mechanisms by which IPMNs give rise to PDAC are incompletely defined. We hypothesize that SMAD4 signaling is specifically involved in IPMN pathway with PanINs and IPMN having partially overlapping signaling pathways and molecular markers. Methods: We performed immunohistochemistry staining on different precursor lesions of mouse pancreatic tissue (PanIN precursor: Ptf1a Cre LSL-Kras G12D ; IPMN precursor: Ptf1a CreERT LSL- Kras G12D Smad4 fl/fl treated with tamoxifen) using markers of different IPMN subtypes and signaling pathways known to be involved in PDAC including, MUC1, MUC2, MUC5AC, SMAD4, ERK1/2, SOX9, and YAP. We treated IPMN cells lines derived from Ptf1a CreERTM LSL-Kras G12D Gnas R201C mice with TGF-β, BMP-2, or vehicle control and quantified RNA expression of Smad7, Serpine1, Id2, and normalized to Pmm1 expression. We performed a western blot to detect the protein expression of phospho-SMAD1, phospho-SMAD2, SMAD1, and SMAD2. Results: Both PanIN and IPMN mouse models exhibited strong expression of MUC5AC and MUC1, reflecting the pancreatobiliary subtype. The tumor cells in both models expressed phosphorylated substrates of protein kinase A, phosphorylated ERK1/2, and SOX9. Regional differences were noted for SOX9 signaling with IPMN demonstrating a greater expression around the outer edges of the lesion, compared to the center. PanIN model demonstrated a more prominent nuclear YAP staining. Treatment of BMP2 and TGF-β in pancreatic IPMN cells from Ptf1a CreERTM LSL-Kras G12D Gnas R201C cell line significantly increased RNA levels of Serpine1 (2.4 and 199.6, respectively; n = 4; p &lt; 0.05) and Smad7 (2.9 and 6.3, respectively; n = 4; p &lt; 0.05). BMP2 treatment significantly increased RNA levels of Id2 (1.9; n = 4; p &lt; 0.05) while TGF-β significantly decreased Id2 level (0.3; n = 4; p &lt; 0.05). Phosphorylated-SMAD2 was detected only with TGF-β treatment while phosphorylated-SMAD1 was detected with vehicle, TGF-β, and BMP2 treatment with the highest level with BMP2 treatment. Conclusions: Knocking out Smad4, concurrent with activating Kras G12D mutation, induces a specific IPMN progression model that shares similar molecular markers as the PanIN progression model, shown in Kras mutation alone. SMAD4 signaling remains intact in IPMN lesions that arise from activating the Kras G12D Gnas R201C mutation, possibly suggesting that Smad4 mutation induces the IPMN-PDAC progression model that differs from Gas-cAMP-PAK-YAP1 cascade found in GNAS signaling.
Analysis of the treatment outcome of ampulla of Vater carcinoma and the usefulness of postoperative adjuvant chemotherapy.
Authors: Shinichiro Ogawa, Tomohiko Adachi, Hajime Matsushima, Hajime Imamura, Koki Kurotaki, Masayuki Fukumoto, Kyohei Yoshino, Takahiro Enjoji, Hanako Tetsuo, Ryo Matsumoto, Takanobu Hara, Akihiko Soyama, Shinichiro Ito, Masaaki Hidaka, Kengo Kanetaka, Susumu Eguchi
Journal: Journal of Clinical Oncology (2023)

692 Background: Patients with ampulla of Vater carcinoma with lymph node metastasis reportedly have a poor prognosis and require postoperative adjuvant therapy. However, due to the small number of published cases, the efficacy of postoperative adjuvant therapy has not yet been established with a high level of evidence. Objective: The aim of this study was to describe the outcome of patients surgically treated for ampulla of Vater carcinoma in our department, evaluate the effectiveness of adjuvant chemotherapy (AC), and clarify which patient groups may benefit from AC. Methods: The study cohort comprised 46 patients who underwent surgery for ampulla of Vater carcinoma in our department from October 2005 to March 2022. We evaluated the clinicopathological background characteristics (tumor size, gross morphology, pancreatic/duodenal invasion, peripancreatic head lymph node metastasis), overall survival (OS), and relapse-free survival (RFS), and compared the OS and RFS in patients with versus without AC. We then analyzed the factors related to the long-term outcome of patients treated for ampulla of Vater carcinoma. Results: During a median observation period of 33.7 months, the 5-year OS and RFS were 63.1% and 61.7%, respectively. Recurrence was observed in 14 patients (30%), with recurrence occurring less than 1 year postoperatively in seven patients (15%). Fifteen patients received AC (chemotherapy regimen: S-1 in 11 patients, GEM in four). The 5-year OS rates with and without AC were 70.3% and 48.2%, respectively (p=0.093). The 5-year RFS rates with and without AC were 72.5% and 42.8%, respectively (p=0.058). Univariate analysis of the total patient cohort showed that the factors related to 5-year RFS were pancreatic invasion (p=0.01), duodenal invasion (p=0.03), and N+ (p=0.004). In multivariate analysis, the only factor related to 5-year RFS was N+ (HR 3.53; 95% CI, 0.99–12.6; p=0.03). The 5-year OS rates in patients with and without N+ were 77.1% and 42.7%, respectively (p=0.04). The 5-year RFS rates in patients with and without N+ were 80.4% and 32.1%, respectively (p=0.004). Conclusions: AC showed a tendency to be effective in preventing postoperative recurrence of ampulla of Vater carcinoma. AC may be particularly beneficial in N+ cases.
Tumor mutation burden in colorectal cancers with POLE exonuclease and non-exonuclease domain variants.
Authors: Salena Ringenbach, Shreya M. Shah, Elena Demidova, Bulat Faezov, Mark D. Andrake, Pilar Mur, Joanne Xiu, Wolfgang Michael Korn, Sanjay Goel, Heinz-Josef Lenz, John Marshall, Anthony Frank Shields, Matthew James Oberley, David Spetzler, Laura Valle, Roland Dunbrack, Michael J. Hall, Sanjeevani Arora
Journal: Journal of Clinical Oncology (2023)

224 Background: Driver mutations in the exonuclease domain (ExoD) of DNA polymerase epsilon ( POLE) have been associated with high tumor mutation burden (TMB). High TMB is an important marker for immunotherapy, and thus understanding the mechanisms that lead to high TMB is an area of active investigation. Many tumors with POLE ExoD driver mutations have additional POLE variants of uncertain significance (VUS). Some of these VUS lie within the ExoD, while most lie outside the ExoD. This study investigates the role of such POLE VUS on TMB and POLE functionality of ExoD-mutated tumors. Methods: Retrospective colorectal cancer (CRC) genomic profiles from Caris Life Sciences (n=1,870) were separated into groups based on the presence of POLE ExoD mutations and the TMB status. Groups were defined as: ‘TMB-high (TMB-H) POLE ExoD driver without additional POLE VUS’, ‘TMB-H POLE ExoD driver plus POLE VUS’, and ‘TMB-low (TMB-L) POLE variant(s) without ExoD driver’. An additional group with ‘TMB-H POLE variant(s) without ExoD driver’ was identified as potentially novel drivers for future study. The microsatellite instability status (MSI or MSS) was also considered. The level of TMB, the presence of polymerase proofreading-associated mutational signatures and POLE stability/functionality analyzed using AlphaFold2 models and Rosetta Molecular Modeling Suite, were evaluated. Results: POLE variants were identified in 4.9% of the CRCs studied (92/1870). In all, 52.2% (48/92) of those tumors were TMB-H, and 38.0% (35/92) of them contained POLE ExoD drivers. The highest median TMB (mTMB) was found in the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, and this was significantly different from the ‘TMB-H POLE ExoD driver without additional POLE VUS’ and the ‘TMB-L POLE variant without ExoD driver’ group, even when MSI tumors were excluded (p&lt;0.001, Mann-Whitney). These results were validated in TCGA CRC tumors and in other tumor types. Within the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, the mTMB increased with the number of accumulated POLE VUS (p&lt;0.001, Mann Whitney). The nucleotide sequence context of 77.8% of the POLE VUS matched mutational spectra associated with POLE ExoD defects, suggesting that most of the POLE VUS are secondary to the ExoD driver mutation. Finally, the majority of POLE VUS within ‘TMB-H POLE ExoD driver plus POLE VUS’ group have a predicted effect on POLE stability and/or function. Conclusions: Our results suggest that the presence of secondary POLE non-driver variants increase TMB in POLE ExoD-mutated tumors. Although still preliminary, these data could impact prognosis and response to immune checkpoint inhibitors in patients. [Table: see text]
Proteomic profiling of antibody-drug conjugate (ADC) biomarkers in pancreatic cancer.
Authors: Sheeno P. Thyparambil, Wei-Li Liao, Robert Heaton, Amanda Strasbaugh, Marya Abebe Melkie, Xuefeng Ling
Journal: Journal of Clinical Oncology (2023)

671 Background: Pancreatic cancer (PaC) is a highly fatal disease with a 5-year survival rate of 5-10%. Effective screening is not available, and most patients (50-55%) present with metastatic (50%-55%) disease at diagnosis. For patients with advanced PaC, the standard chemotherapy combinations include FOLFIRINOX and/or gemcitabine/nab-paclitaxel which has results in a overall survival of 7-11 months. The lack of effective therapies underscores the importance of exploring other agents. We propose that quantitating therapy-associated protein biomarkers including markers of antibody-drug conjugates (ADC) can improve treatment personalization for PaC. Methods: FFPE tumor tissues from 185 clinical PaC patients were microdissected and solubilized for mass spectrometry-based targeted proteomic analysis. We quantified biomarkers for ADCs simultaneously from 2-3 section of FFPE. These biomarkers include antibody targets such as EGFR, HER2, HER3, FRalpha, and Trop2 and payload biomarkers of sensitivity (TOPO1) and resistance (TUBB3). The multiplexed assay also quantified additional 65 clinically relevant protein biomarkers for chemotherapy, immunotherapy and targeted therapy. Results: Expression of EGFR was observed in majority of samples (88%) while only overexpressed ( &gt; 1000 amol/µg) in 3% of samples. HER2 was expressed in half of patients (52%) and overexpressed ( &gt; 750 amol/µg) in 5% of cases while the rest of HER2 protein expression ranged from 300 -750 amol/µg which corresponds to low Her2 expression. Trop2 was expressed in majority of patients (91%) with a 25x distribution between lowest and highest expressor. Other ADC biomarkers include HER3(55%, 5x), Axl (24%, 12x), Mesothelin (65%, 58x), Folate receptor alpha (10%, 17x). Expression of TUBB3 (77%, 8x) and TOPO1 (92%, 8x) in antibody target-positive subset may suggest resistance or response for several known payloads, such as taxanes and irinotecan/deruxtecan/govitecan, respectively. Conclusions: There is currently no approved ADC for pancreatic cancer, but several ADC clinical trials are underway. Quantitative proteomics identified antibody targets as well as markers of resistance or response to payloads for a variety of approved and investigational ADC therapies, which could aid in patient stratification in ADC clinical trials.
The role of education in adjusting to changes in clinical practice for gastric or gastroesophageal junction adenocarcinomas.
Authors: Tariqa Ackbarali, Yelena Y. Janjigian, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2023)

470 Background: Gastric or gastroesophageal junction (GEJ) adenocarcinomas are difficult to treat and associated with poor prognosis, specifically in advanced disease. Recently approved and investigational immune checkpoint inhibitors (ICIs) and HER2-directed antibody-drug conjugates (ADCs) are changing the treatment landscapes for gastric cancer and GEJ cancer, allowing clinicians to manage difficult-to-treat patients. However, these advances also create knowledge and practice gaps that pose many challenges warranting education to close these gaps and to assess current practices. Methods: PlatformQ Health’s proprietary workflow digital technology was utilized to launch a 4-part CME series online in December 2021 which remains on-demand through December 2022 at OMedLive.com. Each module focused on the following topics: 1) HER2 testing, 2) Current care for HER2+ gastric or GEJ cancer, 3) Treatment for unresectable disease and trastuzumab-resistant disease, and 4) adverse event management. This series was conducted in partnership with the American Gastroenterological Association and accredited by the Postgraduate Institute for Medicine. Clinicians engaging in this educational series were assessed at pre- and immediate post-activity. Practice pattern insights and education impact were assessed post-activity. Results: To date, 2,568 US-based clinicians have participated in the educational series. All 6 questions across the 4 modules in the series showed significant improvements in knowledge and competence related to HER2 testing, defining the standard of care, treatment beyond trastuzumab resistance, treatment for unresectable disease, and managing adverse events. Provider insights evaluated post-series revealed 41% of clinicians will consult with a pulmonologist upon development of interstitial lung disease; 51% identified trastuzumab deruxtecan as a novel HER2-targeted therapy having the greatest potential to improve patient outcomes; and 26% reported not repeating HER2 expression testing following progression on a trastuzumab-containing regimen. Evaluating the impact of the educational series, 88% of clinicians reported a positive impact on patient experience and 94% on clinical practice change following participation. The qualitative data depicting the reported impact will be shared. Conclusions: This serialized education was effective in improving knowledge and competence across four major themes of practice within gastric and GEJ cancer management. Provider insights revealed practice shifts following participation and practice impact assessments demonstrated the rapid application of real-time digital education.
Effect of spatial transcriptomic-derived intrinsic epithelial signatures on immune cell recruitment and behaviour in the microenvironment of colorectal cancer.
Authors: Colin Wood, Phimmada Hatthakarnkul, Holly Leslie, Assya Legrini, Andrew Cameron, Kathryn AF Pennel, Owen J Sansom, Joanne Edwards, Nigel Balfour Jamieson, Colin William Steele
Journal: Journal of Clinical Oncology (2023)

251 Background: Colorectal Cancer (CRC) remains a significant healthcare problem. Interest in the role of the Tumour Microenvironment (TME) in progression and metastasis is established, yet much remains to be learned about the mechanism of immune cell recruitment to the TME of primary and metastatic tumours. The Klintrup Makinen (KM) score measures the density of immune infiltrate to the invasive edge of tumours and is associated with good prognosis in primary CRC. Neutrophil infiltration to metastases is a poor prognostic feature suggesting phenotypic differences in the TME at primary and metastatic sites. We set out to examine epithelial determination of the TME in primary CRC. Methods: 180 patient’s primary CRC from a curated TMA underwent deep phenotyping using a multiplex-immunofluorescent panel (DAPI, Panck, CD3 (T cells), FOXP3 (T regulatory cells), CD68 (Macrophages), CD163 (Tumour associated macrophage), CD66b (Neutrophils), KI67). The Nanostring GeoMx Spatial Transcriptomic platform was used to obtain segmented (Tumour: Panck+; TME: Panck-) whole transcriptomic (18000 genes) readout from 54 matched cores from the same TMA. Results: No significant association was demonstrated between immune cell density of any cell types and clinicopathological variables including tumour side, MMR status, N-stage or survival. High KM grade was associated with high CD3 (P = 0.01) and FOXP3 (P = 0.002). Density of all immune cell types were highly corelated. Spatial transcriptomic analysis of the segmented epithelium of patients with high KM grade demonstrated over-expression of known neutrophil chemo-attractant CXCL5 (log2FC 3.76 Adj.P &lt; 0.005). The TME compartments of cores with high CD68 and low CD163 counts were associated with adaptive immune co-ordination with high expression of CXCL13 (log2FC -2.97, Adj.P &lt; 0.005) and CD74 (log2FC -1.42 Adj.P 0.007). IGF2 (log2FC 6.08 Adj.P &lt; 0.005) and LCN15 (log2FC 4.96 Adj.P &lt; 0.005) were globally over-expressed in both TME and epithelium of cores with generalised low immune infiltration. The epithelial compartment neutrophil dense cores also over-expressed IGF2 (log2FC -3.53 Adj.P 0.02). Conclusions: TMAs provide a unique opportunity for broad transcriptomic phenotyping of large numbers of patients simultaneously. The Nanostring GeoMx platform is a flexible tool which can be used in novel ways with other proteomic technologies to drive deeper analysis of the TME. CXCL5 expression in the epithelial compartment drives global immune infiltration to the TME and may be manipulated in different contexts therapeutically through CXCR2 signalling in future.
Neo-AEGIS (Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Final primary outcome analysis.
Authors: John V. Reynolds, Shaun R. Preston, Brian O'Neill, Maeve Aine Lowery, Lene Baeksgaard, Thomas Crosby, Moya Cunningham, Sinead Cuffe, Gareth Owen Griffiths, Rajarshi Roy, Stephen Falk, George Hanna, Frederick R. Bartlett, Imelda Parker, Alberto Alvarez-Iglesias, Magnus Nilsson, Guillaume Piessen, Signe Risum, Narayanasamy Ravi, Raymond S. McDermott
Journal: Journal of Clinical Oncology (2023)

295 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) remains controversial, specifically whether multimodal therapy or perioperative chemotherapy is superior. Neo-AEGIS was designed as the first randomized clinical trial (RCT) to directly compare the multimodal CROSS regimen (carboplatin/paclitaxel, 41.4Gy radiation therapy) with a modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) regimen (pre-2018) and more latterly the FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin) regimen. Methods: 377 patients with cT 2-3 N 0-3 M 0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5% for peri-operative chemotherapy. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 34.2 (0.43-111.8) months, there were 186 deaths, 91 CROSS and 95 MAGIC/FLOT arm, with 3-year estimated survival probability of 57% (95% CI 49,64) and 55% (95% CI 47,62), respectively [(HR 1.03 (95%CI. 0.77-1.38))]. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy in the primary outcome of overall survival, notwithstanding greater proxy markers of local tumor response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in clinical decision making in modern practice. Clinical trial information: NCT01726452 . [Table: see text]